Nakken Sigrid, Eikrem Øystein, Marti Hans-Peter, Beisland Christian, Bostad Leif, Scherer Andreas, Flatberg Arnar, Beisvag Vidar, Skandalou Eleni, Furriol Jessica, Strauss Philipp
Department of Clinical Medicine, University of Bergen, 5021, Bergen, Norway.
Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway.
Cancer Cell Int. 2021 Dec 20;21(1):690. doi: 10.1186/s12935-021-02395-9.
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in "low-risk" patients who were potentially eligible for adjuvant treatments or more intensive follow-up.
We assembled a cohort of ccRCC patients (n = 443) and identified all "low-risk" patients who later developed progressing tumors (n = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these "low-risk" patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas.
Principal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p = 2.44E-7).
AGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as "low risk" at the time of surgery.
透明细胞肾细胞癌（ccRCC）是肾癌最常见的亚型，也是最常见的癌症之一。虽然局限性ccRCC患者的生存率较高，但转移性疾病患者的生存率则不然，30%的ccRCC患者在随访期间会发生转移。尽管目前的评分方法能够准确识别低进展风险的患者，但仍有一小部分此类患者会发生转移。因此，我们旨在识别“低风险”患者中的ccRCC进展生物标志物，这些患者可能有资格接受辅助治疗或更密集的随访。
我们组建了一个ccRCC患者队列（n = 443），并识别出所有后来发生肿瘤进展的“低风险”患者（n = 8）。随后，我们对这些“低风险”患者以及16例未进展至复发转移的匹配患者在初次手术时获取的福尔马林固定样本进行了全基因组表达谱分析。这些患者在Leibovich评分、肌酐、年龄、性别、肿瘤大小和肿瘤分期方面进行了匹配。关键结果通过qPCR以及来自癌症基因组图谱（The Cancer Genome Atlas）的外部数据得以证实。
主成分分析表明，在初次手术时就已能检测到系统性的转录组差异。1167个基因，主要与癌症和免疫相关通路有关，在进展者和非进展者之间存在差异表达。对一个分类器的搜索显示，反义长链非编码RNA AGAP2-AS1的过表达能够在转移发现前数年（平均4.5年）正确分类24个样本中的23个，且无需更大的基因面板。随后，我们通过qPCR在相同样本中证实了AGAP2-AS1基因的过表达（p < 0.05）。此外，在来自癌症基因组图谱的外部数据中，AGAP2-AS1的过表达与ccRCC患者总体不良生存结局相关，无论其他预后预测指标如何（p = 2.44E-7）。
AGAP2-AS1可能代表一种新型生物标志物，可识别目前在手术时被归类为“低风险”的高风险ccRCC患者。
